Deficiency of the Lysosomal Protein CLN5 Alters Lysosomal Function and Movement

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Batten disease is a rare, fatal childhood neurodegenerative disorder.
• CLN5 Batten disease, caused by CLN5 gene mutations, involves lysosomal defects and neuronal dysfunction.
• Lysosomal pathology is central to neurodegeneration, but specific mechanisms in CLN5 Batten disease require further elucidation.

Purpose of the Study:

• To investigate lysosomal changes in CLN5-deficient human neurons.
• To model CLN5 Batten disease using human induced pluripotent stem cell-derived neurons.
• To identify novel cellular phenotypes associated with CLN5 deficiency.

Main Methods:

• Generated human cortical-like glutamatergic neurons from induced pluripotent stem cells.
• Utilized CRISPR interference (CRISPRi) to inhibit CLN5 gene expression.
• Assessed lysosomal function and morphology using microscopy and flow cytometry.

Main Results:

• CLN5-deficient neurons exhibited reduced acidic organelles and lysosomal enzyme activity.
• A novel phenotype of impaired lysosomal movement was observed in CLN5-deficient neurons.
• These findings highlight significant lysosomal dysfunction in a human neuronal model.

Conclusions:

• CLN5 deficiency in human neurons leads to reduced lysosomal acidity and enzyme function.
• Impaired lysosomal trafficking is a previously unreported feature of CLN5 Batten disease.
• This study provides critical insights into the lysosomal pathology underlying neurodegeneration in CLN5 Batten disease.